Several studies suggest that the peroxisome proliferator-activated receptor gamma (PPARγ) is involved in atherogenesis. The Pro12Ala polymorphism in the gene encoding PPARγ (PPARγ2 gene) influences the risk for type 2 diabetes. Two population-based studies have shown that the Ala allele is associated with reduced carotid intimal-medial thickness (IMT). However, studies focusing on acute clinical events have yielded conflicting results. Our aim was to evaluate the role of the Pro12Ala PPARγ2 polymorphism on the risk of coronary artery disease (CAD) in an Italian population with a case-controlled genetic association study in which 478 CAD patients and 218 controls were genotyped for the Pro12Ala polymorphism. CAD was diagnosed by angiography. We found that homozygotes for the Ala12 allele had a significantly reduced risk of CAD after adjusting for diabetes, sex, age, body mass index (BMI), smoking, lipids and hypertension (OR = 0.007; 95% C.I. = 0.00–0.32 p < 0.011). In this casecontrol study, homozygosity for the Ala allele at codon 12 of the PPAR 2 gene resulted in reduced risk of CAD. This is consistent with reports from previous studies focusing on atherosclerosis and myocardial infarction.